Liver transplantation is the only curative option for liver failure, which is currently limited by organ shortages. Although liver tissue engineering (LTE) with a strategy of decellularization/recellularization opens a new window to overcome this limitation, its challenges include the lack of specific seed cell sources and appropriate methods to support recellularization. In this preliminary study, both in vitro and in vivo experiments were performed. In vitro, we used novel off-liver progenitors of liver sinusoidal endothelial cells (LSECs) isolated from bone marrow mesenchymal stem cells (NG2/BMMSCs) and a method to establish transplantable biolivers in an advanced decellularized liver scaffold (rDLS). This partial liver scaffolds (rDLS) shows advantages over whole liver scaffolds (nDLS) and also maintains both microvascular network and naturally regenerative microenvironmental niche, enhancing effective recellularization of the NG2/BMMSCs compared to nDLS in reconstructing hepatic main architectures of endothelial, sinusoidal and biliary tree before seeding hepatic stem cells (MLpvNG2 and ratOv cells). The recellularized hepatic stem cells-mediated bioliver was subsequently induced in a 3D bioreactor-like system with three different conditioned media (CM1-CM3) for different culture durations. Importantly, the NG2/BMMSC-lined rDLSs effectively supported the functional bioliver engineering. In vivo, compared with control recipient pigs that underwent ∼90 % hepatectomy only, the recipients subjected to the same hepatectomy and received the bioliver presented greater survival durations. Overall, this study presents a new technology for fabricating a NG2/BMMSC-based transplantable bioliver that may become a promising treatment for liver failure.

This study aimed to identify the worst "bad actors" in mixtures of pollutants contributing to liver damage and shorter telomeres in the U.S. population, using weighted quantile sum (WQS) modeling with stratification by race/ethnicity. We conducted a comprehensive cross-sectional analysis of mixtures of pollutants in National Health and Nutrition Examination Survey datasets: (1) 33,979 adults with blood levels of cadmium (Cd), lead (Pb), and mercury, including subsets with measurements of per-/polyfluoroalkyl substances (PFAS), and polychlorinated biphenyls (PCBs)/polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs); and (2) 7360 adults with measurements of telomeres, Cd, and Pb. Multivariable-adjusted WQS regression examined associations between WQS mixture indices and liver injury (alanine aminotransferase (ALT)-elevation), advanced liver-fibrosis (LF), and telomere length. WQSmetal indices were associated with advanced-LF in all racial/ethnic groups. The top contributor was Cd in the total population and in non-Hispanic Whites (NHW), while Pb was the top contributor in non-Hispanic Blacks (NHB). The WQSmetal-PCB-PCDD/F index was associated with ALT-elevation, with PCB126, Cd and Pb as main contributors; the odds ratio (OR) per decile was 1.50 (95 % CI, 1.26-1.78), while the OR per decile of the WQSmetal-PFAS index was 1.03 (95 % CI, 0.98-1.05), not significant. WQSmetal indices were associated with shorter telomeres. Cd was main contributor associated with advanced-LF in NHW, while Pb was the major bad actor in NHB, suggesting that NHB may be especially susceptible to Pb toxicity. Metals were associated with shorter telomeres. Metal and PCB/PCDD/F mixtures were associated with ALT-elevation. Heavy metals and organic chemicals may contribute to liver-related morbidity and healthcare disparities.

Chronic liver diseases pose a significant global health concern, ranking as the 11th leading cause of death worldwide. It often progresses to organ fibrosis and severe complications such as portal hypertension and cirrhosis. Liver transplantation is the most effective treatment for such diseases, however, the persistent shortage of donors highlights the need for alternatives. Radiofrequency ablation (RFA) is a promising alternative since it is a minimally invasive procedure. RFA uses heat to destroy abnormal tissues. Its benefits include reduced recovery time compared to surgery, precise targeting of affected areas, and long-lasting symptom relief in many cases. However, RFA has challenges, such as potential risks of nerve damage, infection, or incomplete ablation, requiring repeat treatments. Although significant progress in RFA techniques, effective monitoring remains challenging due to the limited ability to accurately characterize the dynamic thermal diffusion and complex tissue responses.

To address this challenge, hyperspectral imaging (HSI) shows promise in monitoring tissue necrosis post-ablation. Our study evaluated HSI's efficacy in monitoring RFA on ex vivo human fibrotic liver tissue samples.

Statistical analysis revealed correlations between spectral patterns and tissue conditions, which helped identify the optimal spectral bands of 543 nm and 579 nm for accurately distinguishing different tissue states. Analyzing the hemoglobin absorption profile indicated significant reductions in absorption of the green light band, showing approximately 40 % reduction in fibrotic tissue and around 20 % reduction in ablated tissue when compared to normal liver tissue. Additionally, a threshold was established for predicting the ablated area of liver samples, ensuring a condition of 90 % specificity.

Consequently, HSI proved to be a valuable tool for monitoring ablation and a step for improving treatment outcomes for liver fibrosis.

The progression from hepatitis to liver fibrosis (LF) and ultimately to hepatic carcinoma (HCC) represents the advanced stages of various liver diseases. Currently, no universal treatment effectively addresses all three conditions. The Traditional Chinese Medicine formula Xiao-Chai-Hu decoction (XCHD) has shown promise in treating hepatitis, inhibiting LF, and serving as an adjunct therapy for HCC. This study evaluates the efficacy and optimal treatment durations of XCHD in managing these liver diseases using meta-analysis and machine learning techniques.

Registered in the PROSPERO database (CRD42024534445), this meta-analysis systematically searched seven databases, including 54 studies with a total of 5,710 patients. Statistical analysis was performed using Stata 17.0. Five machine learning models-Random Forest (RF), XGBoost, Lasso, Multilayer Perceptron (MLP), and a stacking model combining these algorithms-were employed to analyze the data and predict the time-effect relationships. The optimal durations of XCHD treatment for the liver disease trilogy were subsequently projected.

XCHD significantly improved the primary outcome indicators for hepatitis, liver fibrosis, and HCC. Additionally, XCHD demonstrated a beneficial effect on liver dysfunction caused by these diseases. Machine learning predicted the optimal treatment durations of XCHD as 12 weeks for hepatitis, 20.31 weeks for liver fibrosis, and 12 weeks for HCC.

XCHD is effective in treating the liver disease trilogy, with optimal treatment durations of 12 weeks for hepatitis and HCC, and 20.31 weeks for liver fibrosis. These findings support the potential of XCHD in developing precise clinical strategies for managing liver diseases. This study innovatively integrates meta-analysis with machine learning to determine the optimal treatment durations, providing a novel approach for evidence-based precision medicine in Traditional Chinese Medicine.

Acute liver failure (ALF) is a highly lethal condition characterized by massive tissue necrosis, excessive oxidative stress, and serious inflammatory storms, necessitating prompt medical intervention. Although hepatocyte-like cells (HLCs) derived from mesenchymal stromal/stem cells (MSCs) offer a promising alternative cell source for hepatocyte therapy, their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy. To this end, MSCs are bioengineered into multicellular spheroids in the present study. The proteomic analyses and experimental results reveal that extracellular vesicles (EVs) derived from these MSC spheroids (SpEV) contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells, resulting in enhanced pro-angiogenic and antioxidative effects. In addition, MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs, particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement. Following orthotopic implantation in the mouse model, the enhanced paracrine effects of SpEV, combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules (ALL), synergically contribute to the effective amelioration of ALF, highlighting the substantial potential for clinical translation.

Chronic liver diseases are accountable for approximately 2 million deaths annually. The current study aimed to test the putative prophylactic role of Kalanchoe pinnata against hepatic stress.

Kalanchoe pinnata leaf extracts utilized in beverage production were obtained via 3 different extraction techniques (conventional solvent extraction, supercritical fluid extraction, microwave-assisted extraction).

The highest values on 2,2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid assay were from a beverage prepared with supercritical fluid extract. When the prophylactic aspects of a Kalanchoe pinnata-based beverage were explored against carbon tetrachloride- (CCl4-) and gentamicin-induced hepatotoxic conditions in male Wistar rats, results revealed a reduction in serum aspartate aminotransferase, serum alkaline phosphatase, serum alanine transaminase, and bilirubin levels in rats with CCl4 and gentamicin-induced toxicity. The study also concluded that the administration of a therapeutic beverage significantly improved serum total protein, albumin, and globulin levels in Kalanchoe pinnata-treated rats.

Our findings support the ameliorative potential of Kalanchoe pinnata against liver diseases.

Chronic liver disease (CLD) is a substantial cause of morbidity and mortality worldwide. Liver stiffness, as measured by MR elastography (MRE), is well-accepted as a surrogate marker of liver fibrosis.

To develop and validate deep learning (DL) models for predicting MRE-derived liver stiffness using routine clinical non-contrast abdominal T1-weighted (T1w) and T2-weighted (T2w) data from multiple institutions/system manufacturers in pediatric and adult patients.

We identified pediatric and adult patients with known or suspected CLD from four institutions, who underwent clinical MRI with MRE from 2011 to 2022. We used T1w and T2w data to train DL models for liver stiffness classification. Patients were categorized into two groups for binary classification using liver stiffness thresholds (≥ 2.5 kPa, ≥ 3.0 kPa, ≥ 3.5 kPa, ≥ 4 kPa, or ≥ 5 kPa), reflecting various degrees of liver stiffening.

We identified 4695 MRI examinations from 4295 patients (mean ± SD age, 47.6 ± 18.7 years; 428 (10.0%) pediatric; 2159 males [50.2%]). With a primary liver stiffness threshold of 3.0 kPa, our model correctly classified patients into no/minimal (< 3.0 kPa) vs moderate/severe (≥ 3.0 kPa) liver stiffness with AUROCs of 0.83 (95% CI: 0.82, 0.84) in our internal multi-site cross-validation (CV) experiment, 0.82 (95% CI: 0.80, 0.84) in our temporal hold-out validation experiment, and 0.79 (95% CI: 0.75, 0.81) in our external leave-one-site-out CV experiment. The developed model is publicly available ( https://github.com/almahdir1/Multi-channel-DeepLiverNet2.0.git ).

Our DL models exhibited reasonable diagnostic performance for categorical classification of liver stiffness on a large diverse dataset using T1w and T2w MRI data.

Question Can DL models accurately predict liver stiffness using routine clinical biparametric MRI in pediatric and adult patients with CLD? Findings DeepLiverNet2.0 used biparametric MRI data to classify liver stiffness, achieving AUROCs of 0.83, 0.82, and 0.79 for multi-site CV, hold-out validation, and external CV. Clinical relevance Our DeepLiverNet2.0 AI model can categorically classify the severity of liver stiffening using anatomic biparametric MR images in children and young adults. Model refinements and incorporation of clinical features may decrease the need for MRE.

Liver fibrosis is a common pathological condition that is caused by complicated molecular and cellular processes. This study evaluated the therapeutic potential of combined quercetin (QU) with either sildenafil (Sild) or pentoxifylline (PTX) in chronic carbon tetrachloride (CCl4)-induced liver fibrosis in Wistar albino rats. Fibrosis was induced by CCl4 injections (1.5 mg/kg, i.p.) three times weekly for 10 weeks. After six weeks, rats received oral QU (50 mg/kg/day), Sild (50 mg/kg/day), or PTX (10 mg/kg twice/day) individually or in combination for the remaining four weeks. Results showed significant alterations in liver biochemical markers, histopathology, oxidative stress, inflammation, apoptosis, and hypoxic responses due to CCl4 exposure. These changes included reduced expression of Nrf-2, HO-1, and cytoglobin, alongside increased levels of NF-κB, cleaved caspase-3, TNF-α, IL-1β, and HIF-1. Notably, QU, Sild, and PTX, individually or in combination, improved these parameters. The combination of QU with Sild or PTX proved more effective than single treatments, modulating anti-oxidant (Nrf2/HO-1/cytoglobin), anti-inflammatory (NF-κB/TNF-α), and hypoxic signaling pathways (HIF-1α). In conclusion, QU combined with phosphodiesterase inhibitors shows promise as a therapy for liver fibrosis, offering enhanced protection through anti-oxidants and anti-inflammatory mechanisms.

Conventional ischemia-free liver transplantation (CIFLT) represents a pioneering procedure that circumvents ischemia-reperfusion injury to livers throughout the transplant procedure. However, its complexity has limited its widespread adoption. This study introduced a simplified ischemia-free liver transplantation (SIFLT) technique by providing an alternating flow of the portal vein and hepatic artery, demonstrating its efficacy and safety. In this retrospective study, 32 patients who received SIFLT and 32 who received CIFLT were included between January 2021 and January 2024. The intraoperative and postoperative outcomes were collected and elevated. Patients who underwent SIFLT had a shorter anhepatic phase (44.0±2.4 vs. 51.6±2.4 min, p =0.03), along with a comparatively reduced intraoperative blood loss compared to those who underwent CIFLT. Furthermore, the SIFLT group exhibited significantly lower peak AST levels within postoperative 7 days (413.1±62.6 vs. 707.5±110.7 U/L, p =0.02). The incidence of early allograft dysfunction, primary nonfunction, and transplant-related complications were similar across both groups. There were no significant differences in the number of Clavien-Dindo classification of surgical complications and comprehensive complication index at 3 months after transplantation. Kaplan-Meier analysis confirmed similar patient and graft survival rates. The subgroup analysis of extended criteria donor demonstrated that SIFLT can effectively reduce anhepatic phase and intraoperative blood loss and can achieve a clinical prognosis similar to CIFLT. Additionally, histological analysis revealed that both groups demonstrated well-preserved livers and bile ducts. The SIFLT simplifies the intricate surgical procedure while ensuring the protection of livers from ischemia-reperfusion injury. This technique holds promise for enabling patients to achieve clinical outcomes comparable to those of CIFLT.

Metabolic dysfunction-associated steatotic liver disease (MASLD) acts as an alternative for demarcating metabolic dysfunction-associated fatty liver disease (MAFLD). This study aimed to investigate the factors that significantly influence the relationship between MAFLD and MASLD in relation to the incidence of major cardiovascular outcomes.

A total of 340,998 participants in the UK Biobank study were included. Multivariable Cox proportional hazards models were used to estimate the effect of MAFLD and MASLD on the outcomes of cardiovascular diseases (CVDs) (coronary artery disease, stroke, heart failure, and CVD-related death) with hazard ratios (HRs) and 95 % confidence intervals (CIs). A total of 126,077 (36.97 %) participants had MAFLD and 97,418 (28.57 %) had MASLD. Over a median follow-up of 13.5 years (interquartile range 12.6-14.2), there were 41,548 new events of CVDs recorded. MAFLD (HR = 1.52; 95 % CI: 1.49-1.55) and MASLD (HR = 1.42; 95 % CI: 1.39-1.45) were associated with high risks of CVDs. Among the subtypes of MAFLD and steatotic liver disease (SLD), MAFLD diabetes subtype (HR = 2.26; 95 % CI: 2.17-2.35) and alcohol-associated liver disease (ALD) (HR = 1.65; 95 % CI: 1.55-1.76) exhibited the highest risk of CVDs. MAFLD overweight without MD subtype were not associated with CVDs. The effect of MAFLD on the CVD outcomes was consistent regardless of the presence of MASLD.

The metabolic health status and alcohol consumption function as more critical factors than obesity in assessing CVD outcomes in participants with MAFLD or MASLD.

Various types of liver or hepatic diseases cause the death of about 2 million people worldwide every year, of which 1 million die from the complications of cirrhosis and another million from hepatocellular carcinoma and viral hepatitis. Currently, the second most common solid organ transplant is the liver, and the current rate represents less than 10% of global transplant requests. Hence, finding new approaches to treat and prevent liver diseases is essential. In liver diseases, the interaction between the liver, gut, and immune system is crucial, and probiotics positively affect the human microbiota. Probiotics are a non-toxic and biosafe alternative to synthetic chemical compounds. Health promotion by lowering cholesterol levels, stimulating host immunity, the natural gut microbiota, and other functions are some of the activities of probiotics, and their metabolites, including bacteriocins, can exert antimicrobial effects against a broad range of pathogenic bacteria. The present review discusses the available data on the results of preclinical and clinical studies on the effects of probiotic administration on different types of liver diseases.

Liver disease is a growing burden. Transplant organs are scarce. Extracorporeal liver support systems (ELSS) are a bridge to transplantation for eligible patients. For transplant-ineligible patients the objective becomes liver recovery.

We review seven decades of non-cell-based ELSS research in humans. Where possible, we emphasize randomized controlled trials (RCTs). When RCTs are not available, we describe the available human clinical data.

There are three broad cell-free approaches to remove protein-bound toxins (PBTs) and treat liver failure. The first is a dialysate binder suspension. A material that binds the PBT (the binder) is added to the dialysate. Binders include albumin, charcoal, and polystyrene sulfonate sodium. The unbound fraction of the PBT crosses the dialyzer membrane along a chemical gradient and binds to the binder. The second approach is using grains of sorbent fixed in a plastic housing to remove PBTs. Toxin-laden blood or plasma flows directly through the column. Toxins are removed by binding to the sorbent. The third approach is exchanging toxin-laden blood, or fractions of blood, for a healthy donor blood product. Most systems lack widespread acceptance, but plasma exchange (PE) is recommended in many guidelines. The large donor plasma requirement of PE creates demand for systems to complement or replace it.

Now that PE has become recommended in some, but not all, jurisdictions, we discuss the importance of reporting precise PE protocols and dose. Our work provides an overview of promising new systems and lessons from old technologies to enable ELSS improvement.

Fabrication of new 3D scaffold based on sodium alginate (SA), polyvinyl alcohol (PVA), sesame protein isolate (SPI) and Zinc nanoparticles (ZnNPs) has been prepared. SPI was extracted and evaluated via its amino acid composition, solubility, and antioxidant activity. The scaffolds were formulated with different ratios of SA/PVA/Zn/SPI and investigated via different instruments FTIR, XRD and SEM/EDX. Additionally, the effect of the scaffold on the hepato-protection and immune-stimulating in methotrexate (MTX) treated rats has been studied. The results showed that SPI rich in Arginine (21.33 %), Histidine (15 %), Aspartic acid (12.7 %) and Glutamic acid (9.69 %). SPI exhibited higher solubility and antioxidant activity at pH 7 (47.55 and 87.23 %) when measured by DPPH and ABTS methods respectively. SPI and Zn have the ability to mitigate the effects of MTX on body weight loss. SA/PVA/ZnNPs and SA/PVA/ZnNPs/SPI scaffolds have potential liver protection by down-regulating liver functions (34.83 ± 1.17 U/L and 27.83 ± 1.08 U/L, respectively for ALT and 53.00 ± 1.15 U/L and 48.29 ± 1.29 U/L, respectively for AST) and oxidative and inflammatory markers (MDA, IL-6, IL-1β, and TNF-α) and up-regulating liver antioxidant enzymes (GPx and SOD). Furthermore, the immune-enhancing effects of SA/PVA/ZnNPs and SA/PVA/ZnNPs/SPI scaffolds were demonstrated by the reduction in INF-γ (33.17 ± 0.94 pg/mL and 27.73 ± 0.68 pg/mL, respectively) and CD8 (381.5 ± 2.56 pg/mL and 337.8 ± 1.87 pg/mL, respectively) levels and the elevation in CD4/CD8 ratio (1.79 ± 0.02 and 3.00 ± 0.01, respectively) comparable to the MTX group (41.25 ± 0.85 pg/mL, 531.7 ± 2.56 pg/mL and 0.99 ± 0.005, respectively). Thus, the scaffold may have a role in liver protection and immune enhancement.

This study primarily investigated the mechanism and pathways of the cPLA2α signaling pathway on Th17-mediated HSC activation and liver fibrosis, providing insights for clinical strategies to target HSC activation and delay the rapid progression of liver fibrosis. In vitro and in vivo model were established, and different concentrations of the cPLA2α inhibitor AACOCF3 were administered respectively for intervention. The expression of IL- 17 was detected by ELISA, and the expression of cPLA2α protein and HSC activation protein α-SMA index were detected by Western blot and immunofluorescence. In addition, observe the changes in the degree of liver fibrosis in mice through the pathological staining of mouse livers. In an in vitro system, Th17 could induce HSC activation. And after intervention, the results showed that the inhibitor could inhibit Th17 activation of HSC. Next, in an in vivo model, Th17 could also induce HSC activation. And after intervention, the results showed that the inhibitor could also inhibit HSC activation by Th17. Observation under liver pathological staining showed that the inflammation and staining were significantly reduced in the intervention group, suggesting a therapeutic effect of AACOCF3. Using in vitro and in vivo approaches, these data suggest that Th17 cells can promote the activation and proliferation of HSCs, which further exerts a role in promoting liver fibrosis. These data also suggest that the cPLA2α pathway may be involved in the activation of HSCs by Th17 cells and induce liver fibrosis mechanisms.

Yinchenhao Decoction (YCHD), a classic formula in traditional Chinese medicine, is believed to have the potential to treat liver diseases by modulating the Toll-like receptor 4 (TLR4) target. Therefore, a thorough exploration of the effective components and therapeutic mechanisms targeting TLR4 in YCHD is a promising strategy for liver diseases. In this study, the AIGO-DTI deep learning framework was proposed to predict the targeting probability of major components in YCHD for TLR4. Comparative evaluations with four machine learning models (RF, SVM, KNN, XGBoost) and two deep learning models (GCN, GAT) demonstrated that the AIGO-DTI framework exhibited the best overall performance, with Recall and AUC reaching 0.968 and 0.991, respectively.This study further utilized the AIGO-DTI model to identify the potential impact of Isoscopoletin, a major component of YCHD, on TLR4. Subsequent wet experiments revealed that Isoscopoletin could influence the maturation of Dendritic Cells (DCs) induced by Lipopolysaccharide (LPS) through TLR4, suggesting its therapeutic potential for liver diseases, especially hepatitis. Additionally, based on the AIGO-DTI framework, this study established an online platform named TLR4-Predict to facilitate domain experts in discovering more compounds related to TLR4. Overall, the proposed AIGO-DTI framework accurately predicts unique compounds in YCHD that interact with TLR4, providing new insights for identifying and screening lead compounds targeting TLR4.

Chronic liver disease culminates in liver fibrosis, responsible for substantial worldwide morbidity and mortality. Traditional chemical drugs that have proven effective at treating other types of tissue fibrosis may be repurposed for treating liver fibrosis but face inefficient outcomes or elicit undesirable side effects. Hepatic-targeted drug nanocarriers offer a potential strategy for achieving localized drug release to effectively alleviate liver fibrosis while mitigating off-target effects. Elevated levels of fibroblast activation protein-α (FAP-α) have been associated with liver fibrosis and the presence of platelet-derived growth-factor-receptor-β-overexpressing activated hepatic stellate cells. Therefore, FAP-α-responsive nanoshells are developed from hepatic fibrosis targeting peptides to protect and transport pirfenidone (PFD) to fibrotic livers for potentiated therapeutic efficacy. In vitro experiments validate that PFD-loaded hepatic- and fibrosis-targeting nanoshells (PFD@ns) lessen transforming-growth-factor-β1-driven collagen production and activation of hepatic stellate cells. In animal models of liver fibrosis, PFD@ns increase the efficacy of PFD in preventing fibrosis, alleviating proinflammatory cell infiltration, and modulating the PI3K/AKT/mTOR signaling pathway. In conclusion, these findings suggest that the hepatic- and fibrosis-targeted PFD@ns can potentially serve as an effective tool in the treatment of liver fibrosis.

Cirrhosis is a leading cause of morbidity and mortality worldwide, yet preventable at early stages. Currently, effective approaches for early diagnosis are lacking. A novel electrocardiogram (ECG)-enabled deep learning model trained for detection of advanced chronic liver disease (CLD) has demonstrated promising results and it may be used for screening of advanced CLD in primary care.

A pragmatic, cluster randomized trial (NCT05782283) in 45 Mayo Clinic primary care practices will be conducted over a period of 6 months with 6 months of follow up. Care teams will be randomized 1:1 to intervention or usual care, stratified by region and patient volume. Patients from providers enrolled in the trial who undergo an ECG during the study period will be included. In the intervention arm, consenting providers to patients identified as higher risk of advanced CLD based on their ECG will be notified with a recommendation for noninvasive fibrosis assessment. The primary endpoint will be detection of advanced CLD (defined as stage 3-4 on blood- or imaging-based noninvasive liver disease assessment or liver biopsy). Secondary outcomes will include completion of fibrosis assessment tests within 180 days of ECG, new diagnosis of liver disease stratified by etiology and risk factors for CLD, and detection of any liver fibrosis (stages 1-4). Post-study surveys to participating clinicians will be conducted.

Preliminary findings suggest outstanding potential for the use of an ECG-enabled machine learning algorithm for detection of advanced CLD in the primary care community.

Globally, the aetiology and epidemiology of chronic liver disease (CLD) are undergoing significant changes. We aimed to investigate the updated global burden of CLD, evaluate the cross-country inequalities, and provide 2050 predictions.

Using the Global Burden of Disease Study (GBD) 2021 data resources, we analysed and forecasted CLD prevalence, incidence, and related death from 1990-2021 to 2050, respectively. We calculated average annual percent change (AAPC) by joinpoint regression model and quantified inequalities according to World Health Organisation-recommended health equity standards.

In 2021, the number of prevalent, incident CLD and related deaths globally were 1.7 billion (95% uncertainty interval (UI): 1.6-1.8), 58.4 million (95% UI: 54.2-62.8) and 1.4 million (95% UI: 1.3-1.5), respectively. During 1990-2021, the age-standardised incidence rate (ASIR) increased, especially in those aged 15-49 (AAPC: 0.49%; 95% confidence interval [CI]: 0.45%-0.53%), in Europe (AAPC: 0.41%; 95% CI: 0.41%-0.42%) and the Americas (AAPC: 0.41%; 95% CI: 0.39%-0.42%), whereas the age-standardised death rate (ASDR) decreased globally (AAPC: -1.26%; 95% CI: -1.35% [-1.17%]) and across subgroups. During 1990-2021, the ASIR of metabolic dysfunction-associated steatotic liver disease (MASLD) increased the most in those aged 15-49 (AAPC: 0.72%; 95% CI: 0.67%-0.77%) and in the Western Pacific region (AAPC: 0.73%; 95% CI: 0.59%-0.86%). Socio-demographic index (SDI)-related inequalities decreased for the age-standardised prevalence rate (ASPR) and ASIR of CLD but increased for ASDR, placing a disproportionately heavier burden on low-SDI countries. From 2022 to 2050, the ASIR of CLD is projected to increase (AAPC: 0.20%; 95% CI: 0.19%-0.20%), but the ASDR is projected to decline (AAPC: -1.91%; 95% CI: -1.96% [-1.85%]).

This study's findings highlight targeted interventions for CLD disparities, focusing on MASLD management, the younger population (15-49 years), and socio-demographic inequalities.

Ferroptosis, a newly discovered mode of cell death, is a type of iron-dependent regulated cell death characterized by intracellular excessive lipid peroxidation and imbalanced redox. As the liver is susceptible to oxidative damage and the abnormal iron accumulation is a major feature of most liver diseases, studies on ferroptosis in the field of liver diseases are of great interest. Studies show that targeting the key regulators of ferroptosis can effectively alleviate or even reverse the deterioration process of liver diseases. System Xc- and glutathione peroxidase 4 are the main defense regulators of ferroptosis, while acyl-CoA synthetase long chain family member 4 is a key enzyme causing peroxidation in ferroptosis. Generally speaking, ferroptosis should be suppressed in alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver injury, while it should be induced in liver fibrosis and hepatocellular carcinoma. In this review, we summarize the main regulators involved in ferroptosis and then the mechanisms of ferroptosis in different liver diseases. Treatment options of drugs targeting ferroptosis are further concluded. Determining different triggers of ferroptosis can clarify the mechanism of ferroptosis occurs at both physiological and pathological levels.

The metabolic pathway of sulfur-containing amino acids in organisms begins with methionine, which is metabolized to produce important sulfur-containing biomolecules such as adenosylmethionine, adenosylhomocysteine, homocysteine, cystine, and hydrogen sulfide (H2S). These sulfur-containing biomolecules play a wide range of physiological roles in the body, including anti-inflammation, antioxidant stress, DNA methylation, protein synthesis, etc., which are essential for maintaining cellular function and overall health. In contrast, dysregulation of the metabolic pathway of sulfur-containing amino acids leads to abnormal levels of sulfur-containing biomolecules, which produce a range of pathological consequences in multiple systems of the body, such as neurodegenerative diseases, cardiovascular diseases, and cancer. This review traces the milestones in the development of these sulfur-containing biomolecules from their initial discovery to their clinical applications and describes in detail the structure, physiochemical properties, metabolism, sulfide signaling pathway, physiopathological functions, and assays of sulfur-containing biomolecules. In addition, the paper also explores the regulatory role and mechanism of sulfur-containing biomolecules on cardiovascular diseases, liver diseases, neurological diseases, metabolic diseases and tumors. The focus is placed on donors of sulfur-containing biological macromolecule metabolites, small-molecule drug screening targeting H2S-producing enzymes, and the latest advancements in preclinical and clinical research related to hydrogen sulfide, including clinical trials and FDA-approved drugs. Additionally, an overview of future research directions in this field is provided. The aim is to enhance the understanding of the complex physiological and pathological roles of sulfur-containing biomolecules and to offer insights into developing effective therapeutic strategies for diseases associated with dysregulated sulfur-containing amino acid metabolism.

Hospital admissions for advanced chronic liver disease (ACLD) are associated with increased mortality, disability, a decline in quality of life and significant economic costs. Being admitted to the hospital usually indicates a triggering event that disrupted a previously stable condition, leading to decompensation or complications of ACLD. The most acute and severe manifestation of this imbalance is acute-on-chronic liver failure (ACLF), a syndrome representing a critical juncture. Reliable prognostic stratification of patients admitted with ACLF could facilitate the systematic delivery of tailored care, ranging from palliative care to intensive interventions like extracorporeal liver support devices and prioritised liver transplantation. Disease-specific prognostic tools, such as the Model for End-Stage Liver Disease score, are effective but have limitations, particularly in reflecting a patient's potential for recovery. The concept of the body's functional reserve in the context of ACLD/ACLF is gaining attention, with the Liver Frailty Index (LFI) potentially emerging as a recommended diagnostic tool.

Patients were selected from our cirrhosis registry (RH7). The LFI serves as an indicator of the patient's prognosis. The LFI measurement takes place at two time intervals: on the patient's admission and after 7 days of hospitalisation.

Our RH7 registry included 154 patients (15.1%) who were diagnosed with ACLF. The primary cause of the underlying ACLD was alcohol-associated liver disease in the majority (79.8%) of cases. The mean value of LFI at admission was 4.50 (± 0.94). When patients with liver cirrhosis were categorised into three subgroups based on the LFI on day 7, survival exhibited a statistically significant decrease (p≤0.05) across all three ACLF grades. This decline in survival was observed from the 'improved LFI' cohort, through the 'stable LFI' group, to the 'worsened LFI' group.

The impact of day 7 LFI on the survival of patients with ACLF is notable. Nevertheless, it does not markedly enhance the predictive capability of the LFI assessed on admission. Consequently, the initial LFI on day 1 continues to be the most valuable and commonly used instrument for promptly recognising individuals with ACLF.

Chronic liver disease is a widespread health problem globally, particularly common in East Asia. Osteoporosis (OP), as a common metabolic bone disease, has also gained increasing attention in aging societies. In recent years, studies have suggested a possible association between chronic liver disease and OP, but their causal relationship has not been fully or systematically studied.

To investigate the causal association between chronic liver disease and OP in East Asian populations using Mendelian randomization (MR) methods.

The datasets for chronic hepatitis B infection (CHB), chronic hepatitis C infection (CHC), and cirrhosis were sourced from the UK Biobank, while those for hepatocellular carcinoma (HCC) and OP were from the Japan Biobank. All participants included were from East Asian populations. We first treated chronic liver disease as the exposure and OP as the outcome for MR analysis, and then performed a reverse analysis treating OP as the exposure and chronic liver disease as the outcome. The inverse variance-weighted (IVW) method was used as the primary method to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). MR-Egger and the weighted median method were used as supplementary approaches to assess the causal association between chronic liver disease and OP. Heterogeneity and pleiotropy tests were also performed to ensure the reliability of the results.

The IVW method results indicated that CHB (ebi-a-GCST90018584) will increase the incidence of OP (bbj-a-137) (OR = 1.063, 95% CI: 1.015-1.112, p = 0.009), with no evidence of heterogeneity or pleiotropy. However, no causal association was found between CHC, cirrhosis, or HCC on OP. Reverse MR analyses did not reveal any significant causal effect of OP on chronic liver disease.

In East Asian populations, CHB will increase the incidence of OP. Therefore, CHB patients not only require long-term antiviral treatment to protect the liver but should also monitor their bone health over time to reduce the risk of OP, ultimately improving quality of life.

Metabolic dysfunction-associated alcohol-related liver disease (MetALD) is an emerging clinical entity that reflects the coexistence of metabolic dysfunction and alcohol-related liver injury. Unlike classical alcoholic liver disease (ALD), MetALD patients often present with lower to moderate alcohol consumption alongside metabolic risk factors such as obesity, insulin resistance, and dyslipidemia. These factors can synergistically worsen liver injury even at lower alcohol intake levels. Alcohol abuse remains a major global health concern, with the liver being the primary target of alcohol's toxic effects. Long-term alcohol exposure, especially when compounded by metabolic dysfunction, can accelerate the progression from steatosis to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Besides alcohol itself, various factors, including genetic predispositions, gender, type of alcoholic beverage, drinking patterns, and co-morbidities such as viral infections (HBV, HCV) modulate disease susceptibility and severity. This review summarizes current knowledge of risk factors contributing to MetALD, highlights the synergistic interactions between metabolic dysfunction and alcohol consumption, and discusses potential strategies for disease prevention and management.

Alcohol-associated liver disease (ALD)-encompassing conditions including steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma-refers to hepatic damage arising from excessive or hazardous alcohol consumption, and is now recognized as a significant global health burden. Although the mechanisms underlying ALD remain incompletely understood, several pathways have been substantiated over the last five decades, notably the involvement of intestinal microorganisms and the involvement of the gut-liver axis in alcohol metabolism and ALD pathogenesis. Ethanol intake disrupts the intestinal microbial balance and compromises the gut barrier, resulting in increased permeability to microbial products. The subsequent translocation of microbial metabolites and other antigenic substances to the liver activates hepatic immune responses, thereby contributing to liver injury. In addition, gastrointestinal hormones are also implicated in ALD progression through various mechanisms. Although no therapies for ALD have been approved by the Food and Drug Administration, various therapeutic strategies targeting the intestinal microbiota and gut barrier have been identified. In conclusion, this review discusses the role of the gut-liver axis in alcohol metabolism and ALD pathogenesis and explores the emerging therapeutic strategies.

The safe and efficient delivery of chemicals and biologics remains crucial for liver disease therapy. In this study, we developed a targeted drug delivery system utilizing a galactose-modified erythrocyte membrane coating technique and drug liposome nanoparticles, which were further optimized using orthogonal experiments and response surface analysis. The specificity, precision, accuracy, and stability exhibited satisfactory performance in bioanalytical analysis. Specifically, targeting ligands (Gal-DSPE-PEG3400) were efficiently inserted into red blood cell (RBC) membranes using a facile insertion method. When Gal-DSPE-PEG3400-RBC was fused with fenofibrate liposome nanoparticles (FNB-Lip) by co-extrusion, the resulting galactose-modified erythrocyte membrane fusion liposome nanoparticles (Gal-RBC-FNB-Lip) showed long-term stability, excellent biocompatibility, prolonged retention time, and superior liver accumulation and therapeutic efficacy. These qualities make it suitable for effective drug delivery. The findings of this study will provide a fundamental basis for research and development of liver-targeted drugs and offer novel insights into the treatment of clinical liver diseases.

Liver necrosis is the irreversible loss of hepatocytes through toxin-induced injury, ischemia, or infection to produce organ dysfunction. It is a significant pathological marker in many liver disorders, including cirrhosis, and hepatitis, and contributes to organ failure and general systemic effects. This research aims to evaluate the protective effects of a newly synthesized compound named 1-(5-((1-(1-(4-((4-(4-(1-((5-acetyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)ethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)sulfonyl)phenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazono)-4-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one (TTTE) sulfone-bis chalcone derivative on liver necrosis caused by TAA therapy using murine model. The research investigates optimal cellular pathways which demonstrate the therapeutic properties of TTTE as a potential treatment for liver injuries. The newly prepared compound TTTE was successfully characterized by Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H-NMR) spectroscopy, carbon-13 nuclear magnetic resonance (13C-NMR), The safety of the as-prepared compound TTTE was determined based on weight changes and the behaviors in all the groups were monitored for 21 days. The effect of treatment of TTTE at different doses (300, 200, and 100 mg/kg B.W.) was studied. High-dose TTTE revealed a 62.5% survival rate compared to the untreated TAA group (40%). Molecular analysis exhibited that high-dose TTTE downregulated Cas-3, TIMP-1, and proinflammatory cytokines (TNF-α, NF-κB, and IL-6) compared to untreated TAA. Results of histopathological and IHC examinations exhibited high TTTE dose have no signs of liver injury with suppression in TGF-β expression as a result of anti-inflammatory response. Our study concluded that the synthesized compound, TTTE has a potential therapeutic strategy in mitigating liver necrosis.

Metabolic dysfunction associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH), is a progressive form of steatotic liver disease (SLD). It is an emerging healthcare threat due its high prevalence, accelerated and non-linear progression, and final culmination as decompensated liver failure and/or hepatocellular carcinoma (HCC). The pathogenesis of NASH is complex with strong ethnic influences and genetic predispositions, underscoring the need for preclinical models that utilize patient-derived cells to enhance our understanding of the disease. Current models face three major limitations: (i) reliance on primary cells with limited reproducibility, high cost, short culture duration and ethical considerations, (ii) failure to recapitulate all key features of NASH, and (iii) inadequate drug testing data and/or data did not correlate with clinical responses. Therefore, there is a pressing need for robust and relevant preclinical models that faithfully recapitulate human NASH, allow generation of patient-specific models and provide quantitative responses for mechanistic studies and drug testing. We have developed a functional liver tissue-on-a-chip by co-culturing human adult liver stem cell (haLSC)-derived hepatobiliary organoids, induced pluripotent stem cell (iPSC)-derived Kupffer cells (iKCs) and iPSC-derived hepatic stellate cells (iHSCs). We simulated the metabolic microenvironment of hyper nutrition and leaky gut by treating the cells with a concoction of free fatty acids (FFAs), fructose, gut-derived lipopolysaccharides (LPS) and a gut-derived metabolite, phenyl acetic acid (PAA). Through optimization of co-culture media and induction regimens, we were able to stably induce steatosis, hepatocellular ballooning, inflammation, and activation of iHSC and fibrosis-all key hallmarks of NASH. Our LEADS (liver-on-a-chip for NASH drug testing) model also recapitulated the pathological types of steatosis and allowed for quantification of the key features via microscopic evaluation and secretome profiling to score for disease severity. Notably, treatment with saroglitazar, pioglitazone, cenicriviroc (CVC), obeticholic acid (OCA) and resmetirom produced responses similar to those observed in clinical trials. Taken together, our LEADS model is the first model developed using patient-derived hepatic stem cells which recapitulated all key features used for comprehensive drug testing, with results matching to clinical responses.

Both metabolic dysfunction-associated fatty liver disease (MAFLD) and gestational diabetes mellitus (GDM) during pregnancy are emerging as an adverse synergistic relationship of growing concern. This narrative review focuses on the maternal and fetal consequences associated with women who have MAFLD and/or GDM during pregnancy, including an exploration of long-term cardiometabolic risks for postpartum maternal and childhood health. We conclude that implementation of a life course approach to management of these high-risk women remains paramount.

This study aimed to perform a systematic review and meta-analysis on the hepatoprotective effects of naringin based on the pre-clinical evidence.A detailed literature search was performed using online databases such as Google Scholar, PubMed, Scopus, and EMBASE. Based on the predefined inclusion and exclusion criteria, 20 studies were considered for meta-analysis.The outcomes of the meta-analysis revealed that naringin improved liver function by reducing the elevated levels of ALT, AST, GGT, LDH, ALP, and bilirubin. It improved the enzymatic and non-enzymatic antioxidants, such as SOD, catalase, GSH, GST, GR, and GPx (p < 0.05 for all the parameters), while reducing the LPO/MDA levels (p < 0.05). NAR treatment also alleviated the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α, p < 0.001 for all the parameters; NF-κB, p = 0.29) in various animal models of liver injury. In addition, NAR significantly reduced the caspase-3 and Bax/Bcl-2 ratio (p < 0.05) compared to the control group. Furthermore, naringin treatment has normalised the liver and body weights compared to the disease control group.This systematic review and meta-analysis demonstrate that naringin significantly improved the liver function in various animal models of liver injury, via potent antioxidant and anti-inflammatory mechanisms.

The liver and kidney are vital organs that are interconnected, dealing with detoxifying and excreting xenobiotics. They are constantly exposed to oxidative stress, which can cause hepatorenal dysfunction. This study compares two forms of Nigella sativa (NS), NS oil (NSO), and NS seeds (NSS), for the first time, in their ability to mitigate hepatorenal injury induced by azathioprine (AZA), exploring potential underlying mechanisms.

Group (1): negative control; Group (2): positive control received 15 mg/kg AZA orally. Groups (3, 4, and 5) received 100 mg/kg silymarin (standard reference), 500 mg/kg NSO, and 250 mg/kg NSS, respectively, and were subjected to the same dose of AZA. A one-way analysis of variance was conducted, followed by Mann-Whitney post-hoc analysis.

Administration of AZA induced hepatorenal dysfunction, evidenced by dyslipidemia, elevations in serum liver enzymes, creatinine, urea, pro-inflammatory cytokines, and cytokeratin-18. Antioxidant enzymes in liver and kidney tissues were reduced, with an elevation in caspase-3 and caspase-9. Both forms of NS significantly balanced serum pro- inflammatory cytokines (14.33 ± 2.33, 15.15 ± 1.64 vs. 24.87 ± 1.87) pg/ml, interleukin-4 (16.72 ± 1.14, 15.95 ± 1.03 vs. 10.64 ± 1.04) pg/ml, and interleukin-10 (19.89 ± 0.69, 18.38 ± 0.38 vs. 15.52 ± 1.02) pg/ml, and downregulated cytokeratin-18 (210.43 ± 21.56, 195.86 ± 19.42 vs. 296.54 ± 13.94) pg/ml for NSO and NSS vs. the positive group, respectively. NSS enhanced liver antioxidant activity (P < 0.05), normalized liver enzymes (P < 0.05, P < 0.01) for alanine aminotransferase and aspartate aminotransferase, respectively, and significantly lessened dyslipidemia (P < 0.05). Liver caspase-3 and caspase-9 improved significantly with NSS, while kidney caspase-3 and caspase-9 improved with NSO. NSO increased kidney glutathione peroxidase and catalase (P < 0.01) and corrected creatinine and urea (P < 0.05). Histopathological observations confirmed the present data.

Conclusively, NSO and NSS mitigated hepatorenal dysfunction responses to AZA through antioxidant, anti-inflammatory, and anti-apoptosis properties that underlie their protective performance. Interestingly, NSO surpassed NSS in restoring renal oxidative damage, while NSS provided better hepatic protection than NSO, suggesting NSO for patients with kidney dysfunction and NSS for those with liver problems.

Liver cirrhosis continues to be a major global health issue, contributing to high morbidity and mortality due to its progressive nature and associated complications. This review explores recent advancements in the diagnosis and treatment of liver cirrhosis and its related syndromes. Non-invasive diagnostic tools, such as elastography and serum biomarkers, have significantly improved early detection, reducing the need for liver biopsies. Advanced imaging techniques, including MRI and CT, further enhance diagnostic accuracy. In parallel, molecular and genomic research is providing new insights into the pathogenesis of the disease, paving the way for precision medicine. On the treatment front, pharmacological innovations, such as antifibrotic agents and targeted therapies, show promise in slowing disease progression. Endoscopic interventions like variceal banding are improving the management of complications, while advancements in liver transplantation and artificial liver support systems offer life-saving alternatives. Regenerative medicine, particularly stem cell therapy and tissue engineering, is emerging as a promising strategy for liver repair. Managing cirrhosis-related syndromes, including portal hypertension, ascites, hepatic encephalopathy, and hepatorenal syndrome, now involves evolving therapeutic approaches such as transjugular intrahepatic portosystemic shunt (TIPS) and novel pharmacotherapies. Prognostic scoring systems like the MELD and Child-Pugh are being refined with new biomarkers for better risk stratification. The future of cirrhosis care will likely involve the integration of artificial intelligence and machine learning for early diagnosis and personalized treatments, alongside emerging therapies currently under investigation. Despite these advancements, challenges such as costs, accessibility, and healthcare disparities remain barriers to widespread adoption. This review highlights the importance of incorporating innovative diagnostic and therapeutic strategies into clinical practice to improve the outcomes for patients with liver cirrhosis and its complications.

This study was conducted to assess the hepatoprotective potential of Annona muricata flower (AMF) using albino rats' model.

Liver function assays such as alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBILI), antioxidants, haematology (HGB), histology, inhibition of transforming growth factor beta receptor I (TGFβR1) and antibacterial assays were investigated.

Induction with acetaminophen gave rise to a significant increase (p < 0.05) in serum of liver enzymes of ALT, AST, ALP and TBILI in the acetaminophen (APAP) only group, which indicates hepatocellular injury, whereas AMF attenuated liver enzymes level. The histological assessment confirmed that AMF possesses blood-enhancing ability. AMF significantly showed inhibition of TGFβR1. AMF was active against all the tested bacteria with high zones of inhibition.

This study provides information on the uses of AMF as a natural product for hepatoprotection and other therapeutic purposes.

The AST/ALT ratio is a biochemical marker associated with poor clinical outcomes in various patients, but its role in severe cirrhosis is unclear. This study investigated the relationship between the AST/ALT ratio and mortality in the intensive care unit (ICU) patients with cirrhosis.

This retrospective cohort study analyzed 2,090 liver cirrhosis patients from the MIMIC-IV database, focusing on their first ICU admission between 2008 and 2019. The AST/ALT ratio, measured within 24 h of admission, was the exposure variable, and the main outcome was 28-day mortality. A multivariable logistic regression model evaluated the link between the AST/ALT ratio and mortality. Nonlinear relationships were explored using smooth curve fitting and saturation effect analyses. Stratified analyses and interaction tests were also performed based on demographic and clinical characteristics.

The study involved 2,090 critically ill liver cirrhosis patients, averaging 59.1 years old, with 65% male and a 28-day post-ICU admission mortality rate of 29%. The AST/ALT ratio was linked to mortality risk (adjusted odds ratio (OR) 1.1, 95% confidence interval (CI) 1.0-1.2; p = 0.015), showing a nonlinear pattern with a critical point at 3.6. Below this, each unit increase raised mortality risk by 40% (adjusted OR 1.4, 95% CI 1.2-1.6, p < 0.001), but the effect plateaued beyond this level (adjusted OR 1.0, 95% CI 0.8-1.1, p = 0.600). Subgroup analyses confirmed the consistent association, with interaction P values over 0.05.

The AST/ALT ratio is an independent predictor of 28-day mortality in critically ill cirrhotic patients, with a nonlinear relationship (risk increases up to a ratio of ~ 3.6, then plateaus). This marker could enhance ICU risk stratification and inform clinical decision-making.

The impact of homelessness on clinical outcomes and health care utilization among hospitalized cirrhosis patients has not been well-characterized.

We conducted a cross-sectional study using the National Inpatient Sample (2016 to 2021) to analyze hospitalizations of adults with cirrhosis, comparing outcomes between those with and without homelessness. Demographic, clinical, and hospital-level characteristics were assessed, along with outcomes such as mortality and AMA discharges. Health care utilization metrics, including length of stay (LOS) and cost, were also evaluated, with multivariable regression used to adjust for confounders.

Among 4,579,858 hospitalizations for cirrhosis, 109,640 (2.4%) involved homeless patients, who were younger (mean 53.5 vs. 60.6 y, P<0.001) and predominantly male (80.4% vs. 58.9%, P<0.001). Homeless patients had higher rates of alcohol use (73.5% vs. 30.9%, P<0.001), opioid use disorder (11.8% vs. 3.6%, P<0.001), and psychiatric comorbidities (62% vs. 37.4%, P<0.001). Hispanic and Native American patients were over-represented, while white patients were under-represented. Mortality was lower in homeless patients (aOR=0.49, 95% CI: 0.45-0.54, P<0.001). However, AMA discharges were significantly higher (9.6% vs. 2.7%, P<0.001). Homeless patients had longer hospital stays (mean 7.3 vs. 6.2 d, P<0.001) but lower per-day hospitalization costs ($2278 vs. $2859, P<0.001).

Despite lower mortality rates and cost per hospitalization day, high AMA discharge rates and prolonged hospital stays underscore the challenges to safe discharge among patients with cirrhosis experiencing homelessness.

As a common cancer, liver cancer imposes an unacceptable burden on patients, but its underlying molecular mechanisms are still not fully understood. Therefore, there is an urgent need to potential biomarkers and diagnostic models for liver cancer.

In this study, transcriptome and single-cell datasets related to liver cancer were downloaded from the UCSC Xena database and the Mendeley database, and differential analysis and weighted gene co-expression network analysis were used to find differentially expressed genes related to liver cancer. We used multiple machine algorithms to find hub genes related to liver cancer, and constructed new artificial neural network models based on their transcriptome expression patterns to assist in the diagnosis of liver cancer. Subsequently, we conducted survival analysis and immune infiltration analysis to explore the correlation between hub genes and immune cells, and used single-cell data to verify hub genes related to liver cancer.

This study identified MARCO, KCNN2, NTS, TERT and SFRP4 as central genes associated with liver cancer, and constructed a new artificial neural network model for molecular diagnosis of liver cancer. The diagnostic performance of the training cohort and the validation cohort was good, with the areas under the ROC curves of 1.000 and 0.986, respectively. Immune infiltration analysis determined that these central genes were closely associated with different types of immune cells. The results of immunohistochemistry and the results at the single cell level were consistent with those at the transcriptome level, and also showed obvious differences between different cell types in liver cancer and healthy states.

This study identified MARCO, KCNN2, NTS, TERT, and SFRP4 from multiple dimensions and highlighted their key roles in the diagnosis and treatment of liver cancer from multiple dimensions, providing promising biomarkers for the diagnosis of liver cancer.

Long-term alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma. Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt hepatocellular carcinoma. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunologic, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix remodeling, and alters hepatocyte cell fate, thereby creating a microenvironment that is highly conducive to carcinogenesis. This article provides a systematic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related hepatocellular carcinoma. In addition, emerging therapeutic strategies that offer potential for early identification and tailored therapy of ALD are explored-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches.

Vitamin D deficiency is prevalent and linked to chronic diseases; its association with advanced liver disease progression requires clarification.

To investigate the association between vitamin D levels and risks of liver cirrhosis, hepatocellular carcinoma (HCC), and mortality, and assess risk changes after achieving sufficiency post-supplementation.

This was a retrospective cohort study.

Utilized TriNetX US data (3,905,594 patients, 2000-2024). Adults with vitamin D deficiency (20.00-30.00 ng/mL) were compared with those with sufficient levels (30.01-80.00 ng/mL). Follow-up was initiated from the first vitamin D test or start of supplementation to minimize immortal time bias. Propensity score matching (1:1) balanced >20 baseline confounders.

After matching, 1,204,760 patients with vitamin D deficiency and 1,204,760 with sufficient vitamin D levels were included. Vitamin D deficiency was associated with an increased risk of liver cirrhosis (hazard ratio (HR), 1.30; 95% confidence interval (CI), 1.25-1.36), HCC (HR, 1.22; 95% CI, 1.08-1.37), and all-cause mortality (HR, 1.14; 95% CI, 1.13-1.16). Achieving sufficient vitamin D levels reduced the risk of all-cause mortality (HR, 0.93; 95% CI, 0.88-0.99) and aligned HCC outcomes (HR, 1.16; 95% CI, 0.68-2.00). However, it did not significantly reduce the risk of liver cirrhosis (HR, 2.05; 95% CI, 1.69-2.50). Dose-response analysis showed a U-shaped relationship for liver cirrhosis and HCC, with the lowest risks at 40-60 ng/mL.

Serum vitamin D levels showed a nonlinear association with liver cirrhosis and HCC risk; deficiency independently increased the risks for cirrhosis, HCC, and mortality. Supplementation achieving sufficiency reduced mortality and normalized HCC risk but not cirrhosis risk, potentially reflecting limitations in reversing established disease. The lowest liver disease risk was associated with vitamin D levels of 40-60 ng/mL in this cohort, although causality and the clinical benefit of targeting this specific range require confirmation.

Recent insights into the immune response in fibrosis have provided valuable perspectives for the treatment of liver fibrosis. Macrophages, as the most abundant immune cells in the liver, are key drivers of liver fibrosis. They are extensively involved in tissue damage, chronic inflammation, and the progression and regression of liver fibrosis. This study aims to conduct a bibliometric analysis and literature review on the mechanisms by which macrophages contribute to liver fibrosis. Specifically, we analyzed a bibliometric dataset comprising 1,312 papers from 59 countries, 1,872 institutions, and 9,784 authors. Keyword co-occurrence analysis identified key research hotspots, including the role of macrophage subtypes in obesity-related metabolic disorders, the crosstalk between macrophages and hepatic stellate cells through mechanoimmunology, emerging strategies for immune modulation targeting macrophages to promote fibrosis regression and liver regeneration, and new discoveries regarding macrophage crosstalk with other immune cells. In conclusion, this study provides a visual analysis of the current research landscape, hotspots, and trends in the field of macrophages and liver fibrosis, and discusses future directions for further exploration in this area.